JPS5914475B2 - Method for producing d,l-norambrenolide - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides decahydro 3 represented by the following structural formula (I).
a, 6, 6, 9a-tetramethyl-(3aα, 5aβ
, 9aα, 9bβ nor(±)-naphtho[2.1-b]furan-2(IH)-one (common name d, l-nor.

The present invention relates to a method for producing ambrenolide (hereinafter referred to as "the present compound"). ★ and (I) The present compound represented by the above structural formula (I) has already been isolated and identified from cigars [H, Kaneko, Agr.
・10Biol, Chem, U, 1461 (1971)
], and is a compound known to impart a pleasant woody aroma to tobacco as a tobacco flavor improver, and to exhibit the effect of suppressing irritation.

[US Pat. No. 2,905,576] This compound has four asymmetric carbon atoms and may have eight stereoisomers, but it is naturally occurring and is known to improve the flavor and aroma of tobacco. The compound is only one in which the moiety forming each condensed ring has a trans configuration as shown in Structural Formula (I). ! 0 Conventionally, the synthesis method for this compound is as follows:
A method using sclareol as a starting material and oxidizing it with chromic acid [L-Ru2ickaet-al, Helv,
Chim-Acta 14, 570 (1931)] is known as an industrial production method; however, this method requires expensive sclareol.

2) Since sclareol is a natural product, the supply of raw materials is unstable.

3) Since harmful chromic acid is used as a reaction reagent, there are environmental hygiene problems.

There are omissions such as n.

The present inventors have conducted extensive research with the aim of overcoming the drawbacks of the above conventional methods and developing a method for economically and industrially efficient production of this compound. The present inventors discovered that the present compound can be easily synthesized in good yield using -β-iononno5 as a starting material, leading to the present invention.

That is, the present invention converts dihydro-β-ionone into βnF, -
After reacting with carboxyethyl triphenylphosphonium chloride to convert it into 4-methyl-6-(2,6,6-trimethylcyclohexenyl)-hexenoic acid, the acid was cyclized using an acid catalyst to form the present compound. The gist is to manufacture.

Next, the present invention will be explained in detail based on the flow sheet shown below.

Note that when naming a compound, the main skeleton portion may be omitted and only the functional group portion may be simplified and described. Dihydro β-ionone () as a starting material of the present invention is a known substance and is known to be easily available as an industrially synthesized product, but it can also be synthesized by the method described below. can. That is, a known method using β-ionone (0 as a raw material [G. Angibeud. et. al, B
ull. SOc. Chim. Fr. 595 (1968)
] to dihydro β-ionone (). Specifically, β-ionone (111) is added dropwise to a mixed bath solution of ethyl ether and hexamethylphosphoric triamide in which metal lithium in which fine pieces are immersed is kept at a temperature of 200 to 30 degrees Celsius. By stirring for 3 hours, dihydro-β-ionone () can be obtained in good yield, which is further purified by vacuum distillation and used as the starting material of the present invention. Next, dihydro β-ionone () is converted to 4-methyl-6-(2,6,6-trimethylcyclohexenyl)-hexenoic acid (5) by the method described below.

Namely, the known substances β-carboxyethyltriphenylphosphonium chloride) and dihydro β-ionone (
) can be converted to acid (IV) in extremely high yields under mild conditions by carrying out the Wittig reaction with l). Phosphonium chloride (7) can be prepared by a known method [D.
B. Dennyet-Al, J. 0rg. Chem27
, 3404 (1962)] Q Komoto, mixing equimolar amounts of triphenylphosphine and β-chloropropionic acid,
By reacting at 145°C to 150°C for 2 hours, it is obtained as white crystals with a yield of about 66 (!) and a melting point of 197°C-199°C.

The starting material, dihydro-β-ionone (), and an equivalent amount of phosphonium chloride (7) are dissolved in an organic bath medium that can dissolve both substances well, such as a mixed solvent of dimethyl sulfoxide and ethers, preferably a pair of dimethyl sulfoxide and tetrahydrofuran. Dissolve in a mixed bath medium of 1.

This bath solution is added dropwise onto 2 equivalents of sodium hydride under an inert gas flow, preferably under an argon flow, under ice-cooling and stirring. The reaction starts to proceed immediately at 20°C to 70°C, but in order to obtain a good yield, it is necessary to keep it at 5°C to 25°C for 1 day or more.
It is desirable to react for 5 days. After the reaction is complete, the reaction solution is poured onto ice, and the reaction product is mixed with a basic water bath solution, preferably about 0.5N sodium hydroxide solution or sodium bicarbonate solution, and an organic bath medium, preferably ethyl ether or ethyl acetate. The acidic components of are extracted into the base/benzened water bath solution. This extract is acidified with a weak acid water bath solution, preferably a 0.5N hydrochloric acid water bath solution to liberate acidic components, and an organic bath medium,
Extraction is preferably performed with ethyl ether or ethyl acetate to obtain crude acid (5). After dissolving this crude acid (5) in an organic bath medium that does not solidify at low temperatures, preferably dichloromethane, O.1 equivalent to 1.00
equivalents, preferably 1 equivalent to 10 equivalents, of a mineral or Lewis acid, preferably stannic chloride or boron trifluoride etherate, at -20°C to -100°C, preferably -78°C (dry ice-ethanol). The present compound Ul) is added under cooling, stirred for 1 minute to 60 minutes, preferably 10 minutes to 20 minutes, poured onto ice, and extracted with an organic bath medium, preferably ethyl ether or ethyl acetate. Obtained in yield (50% to 70% relative to ()).

Although a small amount of impurities are present in the product, they can be easily purified by operations such as chromatography, vacuum distillation, and crystallization. The method of the present invention uses dihythro-β-ionone, which can be obtained at low cost as an industrially synthesized product, as a raw material.
Since the present compound can be stereoselectively synthesized while suppressing the formation of other isomers, it is more economical than conventional methods and is superior in terms of stability of raw material supply.

Furthermore, the reaction does not require high temperatures and pressures, and can proceed in an extremely mild process, and the reaction reagents used in the process do not contain heavy metals, so the possibility of environmental pollution is much lower than with conventional methods. Has a remarkable effect. Example
1 1.94 f1 (10 mm01) of dihythro-β-ionone () and 3.719 (10 mm01) of β-carboxyethyltriphenylphosphonium chloride) were mixed with 20 ml of dry dimethyl sulfoxide and 2 ml of dry tetrahydrofuran.
It was dissolved in 0ml of mixed solvent.

This common liquid was cooled on ice under an argon stream.0.489
(20 mm 01) was gradually dropped onto sodium hydride. After the dropwise addition, the temperature was returned to room temperature (18°C), and stirring was continued for 2 days. The reaction solution was poured onto ice and extracted with 300 d of 5% aqueous sodium hydroxide solution. The extract was washed twice with ether. The extracted water bath solution was acidified with 1N monohydrochloric acid to a pH of ~3, and the liberated acid (]V) was
Extracted with TfL1 ether. The ether layer washed four times with water was dried and concentrated under reduced pressure to obtain 2.159 crude acid (5).

(Yield 86% based on dihythro-β-ionone ()) 1.09 (4 mm01) of this crude acid was dissolved in 5 ml of dichloromethane, and dissolved in dry ice-ethanol for 70 minutes.
Cooled to 8°C.

To this bath solution, 1.1.09 (4 mmOl) of stannic chloride was added dropwise and reacted for 15 minutes with stirring, and then the reaction solution was poured onto ice and extracted with 100 ml of stannic chloride. The extracted ether layer was washed once with 5(f) sodium bicarbonate aqueous solution and three times with water, dried over magnesium sulfate, and then concentrated under reduced pressure to give 0.93f! of product was obtained. This product was crystallized from hexane, and the compound was 0.77
9 (yield 77 (:f/) based on acid (5)) was obtained. The yield of this compound from the starting material was 66%. The obtained physicochemical data of the present compound were as follows, and were completely consistent with the standard sample of the present compound.

Mass spectrometry spectrum: (70eV)m/E25O(M+
), 235, 207, 206, 137, 125, 124
,123,109,95,82,81,69,67,5
5,43,41 Infrared absorption spectrum: (Cm-1) 1775,1432,1400,1392,1238,
1135,1126,1028,959,920 Nuclear magnetic resonance spectrum: (δ) 0.84 (S, 3H), 0.8
8 (S, 3H), 0.91 (53H), 1.33 (S,
3H) Example 2 Dihythro β-ionone of 9.709 (50 mm01) (
) and 18.559 (50 mm 01) of β-carboxyethyltriphenylphosphonium chloride) in 100 ml of dry dimethyl sulfoxide and 100 ml of dry dioxane.
It was dissolved in a mixed solvent of 1.

This solution was cooled on ice under a stream of nitrogen.
00TLm01) onto sodium hydride. After the dropwise addition, stirring was continued for 4 days while cooling on ice. The reaction solution was poured onto ice and extracted with 800a sodium bicarbonate aqueous bath solution. The extract was washed twice with ether. This extracted aqueous solution was acidified with 1N monohydrochloric acid to give a pH of ~3
The liberated acid (5) was extracted with 800 ml of ethyl acetate. The ethyl acetate layer, which had been washed with water six times, was dried over magnesium sulfate and concentrated under reduced pressure to give 8.719 crude acid (I
V) was obtained.

(Yield 700 I for dihythro β-ionone ( )).
8.71f1 (35TrLm01) of this crude acid was mixed with 100ml of dichloromethane. (:.Dissolved, dry ice-
Cooled to -78°C with ethanol. Boron trifluoride etherate 14.29 (100 MmO
1) was added dropwise, and after stirring for 10 minutes, the reaction solution was poured onto ice and extracted with 800 Tn1 of ethyl acetate. The extracted ethyl acetate layer was washed once with a 5% sodium bicarbonate water bath solution.
After washing with water five times, it was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 8.49 g of product. This product was purified by silica gel chromatography using a 9:1 mixed solvent of n-hexane and ethyl acetate.
Crystallization using hexane gave the compound 6.289. (Yield 74(f) based on acid). Yield from starting material was 52%. The obtained physicochemical data of the present compound were completely the same as in Example 1, and completely coincided with the standard sample of the present compound.

Claims (1)

[Claims] 1. Dihydro-β-ionone is reacted with β-carboxyethyltriphenylphosphonium chloride to produce 4-methyl-6-(2,6,6-trimethylcyclohexenyl)-
Decahydro-3a,6,6,9a-tetramethyl-(3aα,5aβ,9aα,9bβ)-(
A method for producing ±)-naphtho[2,1-b]furan-2(1H)-one.